Peripheral Insulin Action Research Articles

Acute effects of exercise on glucose tolerance in non-insulin-dependent diabetes

The evidence that exercise reduces resistant to the action of insulin has generated interest in the possibility that endurance exercise training may be a worthwhile primary therapeutic intervention in the treatment of mild non-insulin-dependent diabetes mellitus (NIDDM). Unfortunately, the results of several studies of exercise training in NIDDM have been discouraging since improvements in oral glucose tolerance (OGT) did not occur or were quite modest even though insulin resistance was reduced. Recently it was determined that 12 months of endurance exercise training at 75-90% of VO2max could normalize OGT in men with mild NIDDM when the post-training OGTT was performed within 18 h of the last bout of exercise. This, coupled with the fact that the enhanced action of insulin is lost in trained persons within a few days of cessation of training, suggests that improved glucose tolerance in NIDDM patients may be partly due to the persistent effects of the last bouts of exercise. Acute exercise in the form of 7 d of intense walking/cycling has been shown to improve glucose tolerance despite a significantly smaller increase in plasma insulin levels during the OGTT in NIDDM. Apparently, the improvement in OGT was due to a decrease in resistance to insulin over the short term since no changes in body weight, body fat, or VO2max took place. Thus, acute exercise of sufficient intensity and duration can increase peripheral insulin action and may contribute to the effects of long-term exercise training on improvement in OGT and the amelioration of insulin resistance in patients with NIDDM.

Effect of physical training on the insulin resistance of aging.

Part of the insulin resistance associated with aging may be attributable to a loss of physical fitness. It was hypothesized that an increase in level of physical training would result in an increase in peripheral insulin action. Eleven healthy 60- to 80-yr-old subjects with normal oral glucose tolerance were studied by a euglycemic two-step hyperinsulinemic clamp before and after 12 wk of physical training. Weight and body composition were held constant, and the clamp was separated by 7 days from the last bout of exercise. There was a positive correlation before training between maximum O2 uptake (Vo2 max) and total body glucose disposal rate (M) at the 40 mU.m-2.min-1 insulin infusion (r = 0.69, P less than 0.02). After training Vo2 max increased 6.7%, M increased 13.4% during the 40 mU.m-2.min-1 and 11.0% during the 200 mU.m-2.min-1 insulin infusion. These results show that peripheral insulin resistance in older persons can be decreased by increasing the level of physical training, independent of changes in weight or body composition. Therefore a part of the insulin resistance of aging is reversible, and level of physical training should be considered in its measurement.

Disopyramide induces insulin secretion and plasma glucose diminution: Studies using the in situ canine pancreas

The mechanism of disopyramide-induced hypoglycemia, a life-threatening complication in the antiarrhythmic drug treatment, is still controversial. To elucidate this, we have evaluated plasma insulin (IRI) and glucagon (IRG) responses in the pancreatic vein (PV) of the in situ pancreas as well as responses of plasma IRI, IRG, and glucose in the femoral artery (FA) to disopyramide phosphate administration in anesthetized dogs. First, infusion of disopyramide at a dose of 50 mg for ten minutes directly into the pancreatic artery, but not the vehicle, increased significantly plasma IRI concentration in the PV ( P < .05 or less), where the IRI response started within three minutes and reached a peak of 2.8-fold preinfusion value at 30 minutes after starting the infusion (n = 7). Plasma IRI concentration in the FA also increased slightly but significantly ( P < .05). Plasma IRG concentration in the PV initially decreased significantly ( P < .05 or less) and in the FA at one point ( P < .05) during the infusion, and then increased significantly after cessation of the infusion, showing a peak of 1.9-fold preinfusion value at 60 minutes in the PV and the FA ( P < .05). Plasma glucose concentration in the FA decreased slowly and significantly after the infusion ( P < .05 or less) and fell by 16% of the baseline value at 60 minutes ( P < .05). Second, infusion of disopyramide at a dose of 7 mg/kg body weight (BW) for ten minutes into the femoral vein induced a peak of serum disopyramide concentration of 13.7 ± 2.8 μg/mL at ten minutes, which corresponds to a twofold to threefold concentration of the human therapeutic level (n = 4). The disopyramide infusion, but not vehicle, induced a significant increment of plasma IRI concentration in the PV at ten minutes ( P < .05), accompanying a very slight IRI rise in the FA. Plasma IRG concentration in the PV again increased after the cessation of the infusion ( P < .05). Arterial plasma glucose level decreased significantly by 14% at 60 minutes ( P < .01). The present results indicate that disopyramide provokes a prompt and significant insulin secretion, and also induces a concomitant fall of plasma glucose level in face of an ongoing IRG secretion. The results thus suggest that the disopyramide-induced glucose fall is caused by decreased hepatic glucose output due to the hepatic action of insulin released by the drug rather than by increased peripheral glucose uptake due to the peripheral action of insulin. It may be an additional explanation for the glucose fall that disopyramide blunts the hepatic glucose output, which should be stimulated by the augmented glucagon secretion. Thus, if combination of the present glucose-lowering factors occurs in the elderly and malnourished patients with the impaired hepatic and renal function, who especially have poor hepatic glycogen storage and gluconeogenic activity, the disopyramide-induced hypoglycemia may easily develop.

Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. Effect of weight loss.

Insulin-stimulated kinase activity of adipocyte-derived insulin receptors is reduced in subjects with non-insulin-dependent diabetes mellitus (NIDDM) but normal in obese nondiabetics. To assess the reversibility of the kinase defect in NIDDM, insulin receptor kinase activity was measured before and after weight loss in 10 NIDDM and 5 obese nondiabetic subjects. Peripheral insulin action was also assessed in vivo by glucose disposal rates (GDR) measured during a hyperinsulinemic (300 mU/M2 per min) euglycemic clamp. In the NIDDMs, insulin receptor kinase activity was reduced by 50-80% and rose to approximately 65-90% (P less than 0.01) of normal after 13.2 +/- 2.0 kg (P less than 0.01) weight loss; comparable weight loss (18.2 +/- 1.5 kg, P less than 0.01) in the nondiabetics resulted in no significant change in insulin receptor kinase activity. Relative to GDR measured in lean nondiabetics, GDR in the NIDDMs was 35% of normal initially and 67% (P less than 0.01) of normal after diet therapy; weight loss in the nondiabetics resulted in an increase in GDR from 53 to 76% of normal (P less than 0.05). These results indicate that the insulin receptor kinase defect that is present in NIDDM is largely reversible after weight reduction. In contrast, the improvement in GDR, in the absence of any change in insulin receptor kinase activity in the nondiabetics, suggests that the main cause of insulin resistance in obesity lies distal to the kinase.

Peripheral and hepatic insulin antagonism in hyperthyroidism.

Eight hyperthyroid and eight normal subjects underwent 2-h oral glucose tolerance tests (OGTT) and euglycemic clamp studies to assess the presence of peripheral and hepatic insulin antagonism in hyperthyroidism. Although the mean total glucose area during the OGTT was similar in the hyperthyroid patients and normal subjects [16.4 +/- 0.8 (+/- SE) vs. 15.8 +/- 0.7 mmol/L.h], the mean insulin area was significantly elevated in the hyperthyroid group (1413 +/- 136 vs. 1004 +/- 122 pmol/L.h; P less than 0.05). Basal hepatic glucose production was measured during the second hour of a primed [3-3H]glucose infusion. A two-insulin dose euglycemic clamp study with [3-3H]glucose and somatostatin (500 micrograms/h) was carried out during the next 6 h. The insulin infusion rate was 0.05 mU/kg.min during the third, fourth, and fifth hours and 0.60 mU/kg.min during the sixth, seventh, and eighth hours. Hepatic glucose production and glucose utilization were measured during the final 0.5 h of each clamp period. Serum C-peptide concentrations were measured in the initial sample and in the last sample of each clamp period. The mean equilibrium serum insulin concentrations were similar in both groups during the final 0.5 h of the low (90 +/- 8 vs. 79 +/- 6 pmol/L) and high (367 +/- 11 vs. 367 +/- 15 pmol/L) insulin infusion rates. Basal serum C-peptide levels were significantly increased in the hyperthyroid patients (596 +/- 17 vs. 487 +/- 43 pmol/L; P less than 0.05) but were suppressed equally in both groups at the end of both clamp periods. The MCRs of insulin were similar in the hyperthyroid and normal subjects during the low (6.7 +/- 1.1 vs. 5.6 +/- 0.5 mL/kg.min) and high (11.9 +/- 0.4 vs. 12.1 +/- 0.5 mL/kg.mm) insulin infusion rates. Glucose production was significantly increased in the hyperthyroid patients during the basal state (17.6 +/- 0.9 vs. 11.5 +/- 0.5 mumol/kg.min; P less than 0.001) and remained elevated during the final 0.5 h of the low (12.1 +/- 1.1 vs. 5.9 +/- 1.7; P less than 0.01) and high (3.2 +/- 1.2 vs. 0.5 +/- 0.3; P less than 0.05) insulin infusion rates. Peripheral insulin action, assessed by Bergman's sensitivity index, was significantly decreased in the hyperthyroid patients (7.4 +/- 2.2 vs. 15.6 +/- 2.1 L/kg min-1/pmol/L; P less than 0.02). In conclusion, hyperthyroidism is characterized by 1) hyperinsulinemia after oral glucose loading, 2) increased basal hepatic glucose production, 3) impairment of insulin-mediated suppression of hepatic glucose production, and 4) antagonism to insulin-stimulated peripheral glucose utilization.

Three Months Energy Restricted Diet Does Not Reduce Peripheral Insulin Resistance in Newly Diagnosed Non Insulin Dependent Diabetics

Sixteen newly diagnosed non insulin dependent diabetic patients were treated for 3 months with an individual energy restricted diet. The effect on weight, hyperglycaemia and insulin response to oral glucose was measured in all subjects, and in 7, peripheral insulin resistance was estimated using a hyperinsulinaemic glucose clamp at two insulin infusion rates (40 and 400 mU m-2 X min-1). After diet, fasting plasma glucose fell from 12.0 +/- 0.7 mmol/l (mean +/- SEM) to 7.4 +/- 0.5 mmol/l (P less than 0.001) and weight fell from 92.9 +/- 4.2 kg to 85.0 +/- 3.1 kg (P less than 0.001). The plasma insulin response to oral glucose was unchanged after diet therapy. Insulin induced glucose disposal (M) was also unaffected by diet at insulin infusion rates of 40 mU m-2 X min-1 (12.5 +/- 1.5 mumol X kg-1 X min-1 vs 15.7 +/- 1.6 mumol X kg-1 X min-1) and 400 mU m-2 X min-1 (49.5 +/- 2.7 mumol X kg-1 X min-1 vs 55.1 +/- 2.5 mumol X kg-1 X min-1). These results show that 3 months reduction of energy consumption with weight loss in newly diagnosed non insulin dependent diabetics improves B-cell responsiveness to glucose but has no effect on liver glucose output or on peripheral insulin action.

The impact of sulfonylureas on hepatic glucose metabolism in type II diabetics.

Fasting hyperglycemia in subjects with NIDDM appears to be the final result of abnormalities in endogenous insulin secretion combined with diminished peripheral insulin action secondary to a combined receptor and postbinding defect in cellular insulin action and accelerated hepatic glucose production. Of these various abnormalities, the accelerated rate of hepatic glucose production appears to be of major importance in determining the overall severity of the hyperglycemia. The hyperglycemia, which is maintained by the accelerated rate of hepatic glucose release, appears to compensate for the decrease in insulin action at the level of the peripheral tissues, as well as the liver. Although this compensatory effect of hyperglycemia appears to match the decrease in insulin action in the peripheral tissues rather precisely, the compensation at the level of the liver does not totally restore normal homeostasis. These observations suggest that the liver and peripheral tissues are intimately linked via mechanisms that remain to be delineated. Recent observations of alterations in the activities of key rate-limiting enzymes in the pathway for oxidiative glucose metabolism suggest that an abundance of glucose precursors may be made in peripheral tissues, which then recycle to the liver to support and/or drive the accelerated rates of hepatic glucose production. Additional studies are clearly needed in these areas to further delineate these crucial issues. In a similar manner, the role of the liver in determining the success of various therapeutic modalities in these subjects appears to be of paramount importance. The data reviewed regarding the mechanisms of action of sulfonylurea agents indicate that the quality of glycemic control achieved in subjects treated with these agents is largely determined by the ability of the drug to lower the elevated rates of hepatic glucose production. This suggests that new compounds that are more effective in this regard will prove to be more efficacious.

Hyperinsulinemia does not compensate for peripheral insulin resistance in obesity.

Based on previous steady-state measures of the biologic activity of insulin, it was thought that postprandial hyperinsulinemia in obesity compensated for insulin resistance. However, we recently demonstrated kinetic defects in insulin action in insulin-resistant nondiabetic obese subjects: activation of insulin-stimulated glucose disposal was slower and deactivation was faster in obese than in normal subjects. In view of these kinetic defects in peripheral insulin action and of the fact that insulin is normally secreted in a phasic manner after meals, we postulated that the hyperinsulinemia of obesity does not compensate for insulin resistance and that the abnormal kinetics of insulin action in obesity are functionally important. To test this hypothesis, oral glucose tolerance tests (OGTTs) were performed in five control (mean age, 33 +/- 2 yr) and five obese (mean age, 41 +/- 5 yr) subjects. All controls had normal glucose tolerance; two obese subjects had normal and three had impaired glucose tolerance. After the results of the OGTTs were available, euglycemic clamp studies were performed in which insulin was infused in a phasic stepped fashion to mimic the rise and fall of mean peripheral insulin levels during the OGTTs. Each subject was clamped at both the "normal" and "obese" OGTT insulin profiles. During the OGTT, glucose and insulin levels were significantly elevated in the obese subjects compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral contraception and insulin sensitivity: in vivo assessment in normal women and women with previous gestational diabetes.

The sensitivity to insulin (euglycemic clamp technique) was assessed in previous gestational diabetic women (n = 6) and nondiabetic women (n = 6) before and twice during low-dose triphasic oral contraceptive administration (ethinyl estradiol and levonorgestrel) for 6 months. Both groups had normal plasma glucose and insulin levels during oral glucose tolerance tests before and during treatment. In vivo peripheral insulin action was measured during insulin infusion of 40 mU/m2 X min with plasma glucose clamped at fasting levels. Before treatment glucose infusion rates were identical in both groups [1.56 +/- 0.12 (SEM) mmol/m2 X min and 1.51 +/- 0.09 mmol/m2 X min, respectively]. After hormonal treatment for 6 months the amount of glucose infused decreased significantly in the previously gestational diabetic women (1.10 +/- 0.12 mmol/m2 X min, P = 0.01), whereas the decrease was less pronounced in the nondiabetic women (1.30 +/- 0.22 mmol/m2 X min, P = 0.09). The decrease in insulin sensitivity was not sufficient to alter glucose tolerance either in the previous gestational diabetic women nor in the nondiabetic women.

Glucose intolerance in Friedreich's Ataxia: Association with insulin resistance and decreased insulin binding

Friedreich's Ataxia (FA) is a neurologic disorder associated with a high prevalence of diabetes mellitus. To assess insulin secretion and insulin resistance, glucose and insulin responses to oral glucose and insulin binding to circulating monocytes and dextran gradient fractionated and unfractionated red blood cells (RBCs) were compared in 11 subjects with FA to 11 age-matched controls. Glucose and insulin responses were elevated from one to three hours after oral glucose in FA. The mean corrected insulin responses were not different while peripheral insulin activity (A) was significantly decreased (1.38 ± 0.22 v 0.77 ± 0.16, control v FA, P < 0.025) indicating the presence of insulin resistance. A significant correlation between the degree of insulin resistance (A) and duration of neurologic symptoms was found ( r = .65. P < 0.025). Resistance to exogenous insulin was confirmed in ten subjects with FA by intravenous insulin tolerance tests (KITT, %/min, 6.25 ± 0.90 v 3.93 ± 0.61, P < .05). Both FA and control groups showed highest insulin binding to fraction A (youngest) RBCs, but no difference was observed between the two groups. However, insulin binding to monocytes was significantly decreased in subjects with FA (% specific binding/10 7 cells/mL, 6.37 ± 0.71 v 4.51 ± 0.39, P < 0.05, control v FA). This was associated with a decrease in apparent receptor affinity. We conclude that FA is associated with insulin resistance, which increases with the duration of neurologic impairment. The insulin binding to monocytes suggests that the insulin resistance may be partially explained by a receptor defect.

Effects of obesity, hyperinsulinemia, and glucose intolerance on insulin action in adipose tissue of sixty-year-old men.

The relative effects of obesity alone, and in combination with fasting hyperinsulinemia and glucose intolerance, on the peripheral action of insulin in adipose tissue were investigated in twenty-four 60-yr-old men, who had been followed for 10 yr. They were divided into four groups of six subjects each on the basis of the following criteria: (1) normal body weight, normal fasting insulin level, and normal glucose tolerance; (2) moderate obesity, normal fasting insulin level, and normal glucose tolerance; (3) moderate obesity, fasting hyperinsulinemia, and normal glucose tolerance; and (4) moderate obesity, fasting hyperinsulinemia, and newly developed, moderate, untreated fasting hyperglycemia and/or glucose intolerance (i.e., mild type II diabetes mellitus). Specific adipocyte insulin binding and the effects of the hormone on adipose tissue lipolysis and glucose oxidation were determined. Insulin receptor binding per cell and per cell surface area were similar in all four groups. Regarding antilipolysis, the insulin sensitivity was the same in all groups and the maximum effect was significantly increased in the three obese groups, as compared with the normal-weight control group. In groups 1-3, insulin stimulated adipose tissue glucose oxidation in a dose-dependent way, and the sensitivity and responsiveness to insulin were comparable. In contrast, in the obese glucose-intolerant subjects (4) there was no significant effect of insulin on glucose oxidation when the hormone was added in increasing concentrations of less than or equal to 35 nmol/L. The basal glucose oxidation was similar in all four study groups. The in vivo insulin tolerance was gradually reduced in groups 2-4, as compared with the normal-weight control group.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo insulin resistance in individual peripheral tissues of the high fat fed rat: assessment by euglycaemic clamp plus deoxyglucose administration.

We have examined peripheral insulin action in conscious rats chronically fed high fat (60% calories as fat) or high carbohydrate (lab chow) diets using the euglycaemic clamp plus 3H-2-deoxyglucose technique. A response parameter of individual tissue glucose metabolic rate (the glucose metabolic index, based on tissue deoxyglucose phosphorylation) was used to assess diet effects in eight skeletal muscle types, heart, lung and white and brown adipose tissue. Comparing high fat with high carbohydrate fed rats, basal glucose metabolism was only mildly reduced in skeletal muscle (only diaphragm was significant, p less than 0.05), but was more substantially reduced in other tissues (e.g. white adipose tissue 61% and heart 33%). No evidence of basal hyperinsulinaemia was found. In contrast, widespread insulin resistance was found during the hyperinsulinaemic clamp (150 mU/l) in high fat fed animals; mean whole body net glucose utilization was 34% lower (p less than 0.01), and the glucose metabolic index was lower in skeletal muscle (14 to 56%, p less than 0.05 in 6 out of 8 muscles), white adipose (27%, p less than 0.05) and brown adipose tissue (76%, p less than 0.01). The glucose metabolic index was also lower at maximal insulin levels in muscle and fat, suggesting the major effect of a high fat diet was a loss of insulin responsiveness. White adipose tissue differed from muscle in that incremental responses (maximal insulin minus basal) were not reduced by high fat feeding. The heart showed an effect opposite to other tissues, with an increase in insulin-stimulated glucose metabolism in high fat versus chow fed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Longitudinal evaluation of the effects of sulfonylurea therapy in subjects with type II diabetes mellitus

Despite more than a quarter of a century of use in managing type II diabetes, the mechanism responsible for the hypoglycemic action of sulfonylurea agents remains controversial. To identify factors responsible for the clinical response to the drug, glycemic control, endogenous insulin secretion in response to mixed meals, adipocyte insulin binding, insulin-mediated peripheral glucose disposal as well as basal hepatic glucose output were assessed in 17 type II diabetic subjects before and after three months of therapy with glyburide, a second-generation sulfonylurea. To determine if the response to the drug changed with time, nine of the subjects were treated for an additional 15 months. Glyburide therapy increased endogenous insulin secretion, increased adipocyte insulin binding after 18 but not three months of therapy, enhanced peripheral insulin action by acting primarily at a post-receptor site, and reduced basal hepatic glucose output. The increase in post-receptor function and the reduction of basal hepatic glucose output appear to be the crucial determinants of the clinical response to the sulfonylurea; the response pattern to sulfonylurea compounds can vary as a function of the duration of treatment. An accelerated rate of basal hepatic glucose output appears to be the major cause of secondary failure in glyburide-treated patients.

Acute reversal of the enhanced insulin action in trained athletes. Association with insulin receptor changes.

We studied the effect of aerobic training and detraining on insulin-stimulated glucose disposal and on erythrocyte insulin receptor binding. Seven endurance-trained athletes were studied at 12 h, 60 h, and 7 days after cessation of training and compared with three untrained, age- and weight-matched controls. The metabolic clearance rate of glucose as measured by the euglycemic clamp technique was 15.6 +/- 1.8 ml/kg/min (mean +/- SEM) in the trained subjects 12 h after the last bout of exercise compared with 7.8 +/- 1.2 ml/kg/min in the untrained control group. When the trained subjects refrained from physical training, the metabolic clearance rate decreased to 10.1 +/- 1.0 ml/kg/min at 60 h and further to 8.5 +/- 0.5 ml/kg/min after 7 days of detraining. The percentage of specific insulin binding to young erythrocytes (density 1.089-1.092), isolated by density gradient centrifugation, decreased from 10.4 +/- 0.9 at 12 h after the last exercise to 8.1 +/- 0.7%/3 X 10(9) cells after 60 h of detraining (P less than 0.001). The decrease in insulin binding to erythrocytes was almost entirely accounted for by a decrease in the number of insulin receptors. We conclude that the increase in peripheral insulin action seen in trained athletes is rapidly reversed, possibly by a mechanism separate from other phenomena associated with chronic training. The parallel findings of decreased in vivo insulin action and decreased insulin binding in young erythrocytes suggest that modulation of in vivo insulin response by detraining may be at least partially mediated by changes in insulin receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin action during pregnancy. Studies with the euglycemic clamp technique.

To assess the mechanisms responsible for the insulin resistance associated with both normal human pregnancy and gestational-onset diabetes, we have measured exogenous glucose disposal using sequential insulin infusions with the euglycemic glucose clamp technique and erythrocyte insulin binding. Three groups of women were studied: nonpregnant women with normal glucose tolerance (N = 7, mean age 32.9 +/- 2.1 yr), pregnant women with normal glucose tolerance (N = 5, mean age 24.8 +/- 3.5 yr), and pregnant women with gestational-onset diabetes (N = 5, mean age 34.6 +/- 2.6 yr). Despite normal plasma glucose levels obtained during a 100-g oral glucose tolerance test, plasma insulin levels were significantly elevated in the pregnant women compared with the nonpregnant control subjects, suggesting a state of insulin resistance. Insulin binding to erythrocytes was similar in all three groups (maximum specific binding being 5.0 +/- 0.6%, 5.5 +/- 1.1%, and 6.0 +/- 0.7% in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively). In vivo peripheral insulin action was measured using the euglycemic glucose clamp technique during an insulin infusion of 40 mU/m2 X min, with blood glucose clamped at a concentration of 75 mg/dl using a variable glucose infusion. Glucose infusion rates were 213 +/- 11 mg/m2 X min, 143 +/- 23 mg/m2 X min, and 57 +/- 18 mg/m2 X min in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates that pregnant subjects display a state of insulin resistance, and that this appears to be more marked in gestational-onset diabetic subjects. To further define the possible mechanism of insulin resistance during pregnancy, the insulin infusion rate was increased to 240 mU/m2 X min and further euglycemic clamp measurements performed. Glucose infusion rates were 372 +/- 11 mg/m2 X min, 270 +/- 31 mg/m2 X min, and 157 +/- 26 mg/m2 X min, in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates a shift to the right of the dose-response curve of insulin action and suggests that the insulin resistance of pregnancy may include a decrease in presumed "maximum" insulin responsivity. In four subjects, studies were repeated in the postpartum period, and these demonstrated that the insulin resistance of pregnancy is ameliorated shortly after delivery. These studies suggest that the insulin resistance of pregnancy results from a target cell defect in insulin action beyond the initial step of insulin binding to cellular receptors, a postreceptor (or postbinding) defect in insulin action.

The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects.

Although sulfonylurea agents have been used in the clinical management of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM) for over two decades, the mechanisms responsible for their hypoglycemic action remain controversial. We have quantitated glycemic control, endogenous insulin secretion in response to mixed meals, adipocyte insulin binding, insulin-mediated peripheral glucose disposal, and basal hepatic glucose output in 17 type II diabetic subjects before and after 3 mo of therapy with the second-generation, sulfonylurea compound glyburide in an attempt to identify the factors responsible for the clinical response to the drug. In addition, 9 subjects were treated for an additional 15 mo to see if the response to the drug changed with time. The mean fasting serum glucose level fell from an initial value of 264 +/- 17 mg/dl to 178 +/- 16 mg/dl after 3 mo of drug therapy. Endogenous insulin secretion increased in all subjects, but the increase was most marked in those subjects who continued to exhibit fasting hyperglycemia (fasting serum glucose greater than 175 mg/dl) after 3 mo of therapy. Adipocyte insulin binding was unchanged after 3 mo of therapy, while the maximal rate of peripheral glucose disposal was increased by 23%, indicating enhancement of peripheral insulin action at a postreceptor site(s). Basal hepatic glucose output showed a significant correlation with the fasting serum glucose level both before and after therapy (r = 0.86, P less than 0.001) and fell from 141 +/- 12 mg/m2/min before therapy to 107 +/- 11 mg/m2/min after 3 mo of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of hyperglycemia on insulin's in vivo effects in type II diabetes.

The present study was designed to quantitate the interaction between the decrease in target tissue insulin action seen in subjects with Type II diabetes and the mass action effect of glucose exerted via the prevailing hyperglycemic state. To this end, euglycemic glucose clamp studies were performed in 26 control subjects using insulin infusion rates of 15, 40, 120, 240, and 1,200 mU/M2 per min and in 10 Type II diabetic subjects using insulin infusion rates of 120 and 1,200 mU/M2 per min. The results of these euglycemic studies indicated that insulin-stimulated peripheral glucose disposal was decreased in the Type II diabetics due to a combined receptor (rightward shift in the dose-response curve) and postreceptor defect in insulin action (decreased maximal response), whereas the decrease in insulin-mediated suppression of hepatic glucose output (HGO) was consistent with a defect in insulin binding (rightward shift in dose-response curve). Hyperglycemic glucose clamp studies were also performed in the Type II diabetics at their respective fasting serum glucose levels (mean [+/- SE] 280 +/- 17 mg/dl) employing insulin infusion rates of 15, 40, 120, and 1,200 mU/M2 per min. In the presence of their basal level of hyperglycemia, the noninsulin-dependent diabetes mellitus (NIDDM) subjects exhibited rates of overall glucose disposal that were similar to those observed in control subjects studied at euglycemia at similar steady state insulin concentrations. This suggests that in Type II diabetics, the mass action effect of glucose partially compensates for the marked decrease in insulin-stimulated glucose uptake observed under euglycemic conditions. However, even in the presence of hyperglycemia, insulin levels below 100 microU/ml had little effect and maximally effective insulin levels increased peripheral glucose disposal only 2.8-fold (142 +/- 7-413 +/- 47 mg/M2 per min) above basal in the Type II diabetics, compared with a sixfold increase (75 +/- 4-419 +/- 34 mg/M2 per min) in the control subjects studied at euglycemia. Thus, the severe insulin resistance that is a characteristic feature of NIDDM remains apparent. Basal HGO was elevated in the NIDDM subjects (157 +/- 6 vs. 76 +/- 4 mg/M2 per min for controls) and a high degree of correlation was found between the basal rate of HGO and the fasting glucose level (r = 0.80, P less than 0.01). The presence of hyperglycemia augmented insulin-mediated suppression of HGO, but did not restore it to normal. We concluded that: (a) in the presence of basal hyperglycemia, physiologic insulin levels exerts a diminished effect to suppress HGO and stimulate peripheral glucose disposal in NIDDM; (b) basal HGO is elevated in untreated Type II diabetics, and this may serve to maintain the level of hyperglycemia required to compensate for the decrease in peripheral insulin action; and (c) fasting hyperglycemia exerts a suppressive effect on HGO but does not completely compensate for the decrease in hepatic insulin action in Type II diabetics.

Influence of aging on insulin receptor binding and metabolic effects of insulin on human adipose tissue.

The influence of aging on the peripheral action of insulin was studied using subcutaneous adipose tissue from eight young (range 22-30 yr) and seven middle-aged (40-59 yr), healthy, normal-weight subjects. Insulin binding per cell was 50% lower in the older than in the younger group (P less than 0.01), essentially owing to a decrease in the insulin receptor number. Concomitantly, insulin sensitivity, as reflected in the degree of antilipolysis and stimulation of glucose oxidation, was 10-20 times smaller in the older subjects (P less than 0.01). Basal lipolysis and the maximum antilipolytic effect of insulin were similar in the two groups. The basal rate of glucose oxidation in the older subjects was less than one-half that for the younger group (P less than 0.025), and the maximum level of insulin-induced glucose oxidation was lower by about 75% (P less than 0.012). Age was significantly and negatively correlated with insulin receptor number (r = -0.81), basal production of 14CO2 (r = -0.73) and maximum level of insulin-induced glucose oxidation (r =- -0.68). The decreases in the receptor number and insulin sensitivity were larger in early adulthood than in the elderly, while the decrease in insulin responsiveness was more uniform. It is concluded that aging is accompanied by impairment of the action of insulin on target cells, owing to alterations at both the receptor and the postreceptor levels. These mechanisms, and especially the postreceptor defect, may be essential factors in the development of relative glucose intolerance in the aged.

Hormonal profile and glucose tolerance in late pregnancy and postpartum.

Oral glucose tolerance, plasma insulin and basal levels of glucagon, hGH, hPRL, hPL, TSH, T4, T3, thyroxine-binding globulin (TBG), cortisol, corticosteroid-binding globulin (CBG) and estriol were measured in 23 normal pregnant women in late gestation (31 +/- 0.4 weeks of pregnancy). Twelve of these subjects could be re-examined 14 +/- 2 weeks postpartum. Blood glucose was lower basal and after glucose load (100 g) in the pregnant group. Fasting plasma insulin and glucose-induced insulin release were higher in pregnancy. The insulinogenic index and the beta cell response were significantly greater antepartum, while peripheral insulin activity was unchanged. The insulin:glucagon ratio as well as TSH and hGH showed no significant differences between ante- and postpartum values. However, T4, T3, TBG, cortisol, CBG, estriol, hPRL and hPL were significantly higher during gestation than after delivery. T4:TBG and T3:TBG ratios were much lower antepartum, while the cortisol:CBG ratio was comparable ante- and postpartum. To our knowledge this is the first report in which such an extensive hormonal and metabolic analysis was performed in the same women ante- and postpartum. It could be shown that glucose tolerance is not worsened during pregnancy in healthy subjects. The higher gestational insulin values are discussed with respect to the various significant hormonal changes.

Insulin resistance in Cushing's syndrome.

It is well established that cortisol excess causes insulin resistance in man, but the mechanisms responsible for this insulin resistance are poorly understood. We studied five women with Cushing's syndrome with impaired oral glucose tolerance tests and seven normal subjects, plotting the shape of the insulin-induced disposal dose-response curve obtained by means of the euglycemic clamp procedure during four different plasma insulin plateaus at four infusion rates of 21, 73, 760, and 1200 mU/M2 . min. Glucose disposal (M = mg/M2 . min) was calculated as glucose amount infused to maintain euglycemia. In Cushing's syndrome the dose-response curve was shifted to the right in comparison with normal subjects, with a significantly lower M (337 +/- 35 vs. 657 +/- 76 P less than 0.01) during the highest insulin infusion rate [maximal glucose disposal (MGD)] without any significant difference in the levels of insulin half-maximally effective in the stimulation of glucose utilization. Neither erythrocyte nor monocyte maximum insulin receptor binding were different between the two populations. Four Cushing's syndrome patients were studied again after surgical treatment. A marked improvement of MGD was observed without any significant change in insulin-binding capacity. These results, particularly the marked decrease in MGD, a typical feature of postreceptor defects, indicate that cortisol-induced insulin resistance in man is due to an impairment of peripheral insulin action located beyond the hormone-receptor binding step.